THE GENETIC EPIDEMIOLOGY OF ASTHMA IN COSTA RICA

本提案旨在研究影响哮喘高风险少数群体（西班牙裔）哮喘发展的遗传因素。为此，我们将集中研究居住在哥斯达黎加中央山谷的高哮喘患病率的遗传孤立西班牙裔人群。为了确定该人群中可能包含哮喘遗传决定因素和相关表型的基因组区域，我们将利用独特的研究设计，收集15个哮喘大谱系（600个个体）和300个无亲缘关系的哮喘儿童及其父母（900个个体）的表型和基因型数据。我们将对这些大谱系进行基因组筛选，我们将对哮喘和7种与哮喘相关的中间表型进行连锁分析，包括气道反应性；FEV 1;支气管扩张剂反应;皮肤试验对常见空气过敏原的反应性；血清总IgE和过敏原特异性IgE；以及外周血嗜酸性粒细胞计数。基因组筛选也将在父母-孩子三人组中进行，祖先的单倍型将被重建，以确定影响哮喘相关表型的区域。在候选区域显示扩展谱系与哮喘和/或哮喘相关表型的联系，以及在不相关的哮喘受试者中存在显著的连锁不平衡，将通过检测与位置候选基因中的单核苷酸多态性的遗传关联来进行精细定位。通过利用一个独特的研究设计，在一个遗传隔离的人群中使用大样本量，我们应该能够解决一个重要但研究不足的问题：遗传对西班牙裔哮喘表型表达的影响。因此，这一建议将大大有助于我们了解西班牙裔美国人支气管哮喘这一重大公共卫生问题的发病机制。

This proposal seeks to examine the genetic factors that influence the development of asthma in a minority group at high risk for the disease (Hispanics). To this end, we will concentrate on a genetically isolated Hispanic population with high asthma prevalence living in the Central Valley of Costa Rica. To identify regions of the genome likely to contain genetic determinants of asthma and associated phenotypes in this population, we will utilize a unique study design that entails collection of phenotypic and genotypic data on 15 large pedigrees multiplex for asthma (600 individuals) and 300 unrelated asthmatic children and their parents (900 individuals). We will conduct a genome screen on these large pedigrees, and we will perform linkage analysis of asthma and seven intermediate phenotypes related to asthma including airway responsiveness; FEV 1; bronchodilator responsiveness; skin test reactivity to common aeroallergens; serum total and allergen-specific IgE; and peripheral blood eosinophil count. A genome screen will also be conducted in the parent-child trios, and ancestral haplotypes will be reconstructed to identify regions influencing asthma- associated phenotypes. Within candidate regions demonstrating both linkage in extended pedigrees to asthma and/or asthma-related phenotypes and significant linkage disequilibrium within the unrelated asthmatic subjects, fine mapping will be performed by testing for genetic association to single nucleotide polymorphisrns within positional candidate genes. By utilizing a unique study design with a large sample size in a genetically isolated population, we should be able to address an important but insufficiently studied problem: the genetic influences on the expression of the asthma phenotype in Hispanics. Thus, this proposal will greatly contribute to our understanding of the pathogenesis of a significant public health problem among Hispanic Americans: bronchial asthma.